The goal of this proposal is to investigate the modulation of neuronal toxicity by the interaction of human matrix matalloproteinases (MMPs) with viral proteins from the human immunodeficiency virus (HIV), particularly the HIV transactivator protein, Tat. HIV infection frequently causes a dementing illness, the pathogenesis of which remains poorly understood. It has only recently been recognized that MMPs have extensive interactions with host proteins, such as chemokines (Zhang et al, 2003) and integrins (Conant et al, 2003), to cause neurotoxicity. However, the possibility that MMPs interact with viral proteins has not been studied. Both Tat and MMPs have neurotoxic properties, which we propose play a role in the development of HIV dementia. Preliminary studies suggest that MMPs and HIV-1 Tat protein interact to modulate neurotoxicity. In the proposed studies, we will further characterize this interaction. Because humans are the only host for HIV infection, we will use a human neuronal cell culture system. We will determine the mechanisms of interaction, leading to subsequent neurotoxicity. Such mechanisms may include cleavage or alteration of Tat by MMPs through direct protein-protein interaction, the ability of Tat to modulate the expression and release of MMPs extracellularly, and alteration of receptor mediated signaling cascades resulting in increased oxidative stress and subsequent neuronal dysfunction. We also propose to explore potential targets for HIV dementia therapy within the framework provided by Tat-MMP interactions. Importantly, this proposal includes a detailed career development plan. The diverse clinical experience, emphasis on teaching, and vibrant neuroscience environment, with special expertise in neuro-infectious diseases, provided by Johns Hopkins Neurology, and Dr. Avindra Nath's laboratory in particular, will provide me with the guidance and opportunities that I need to become a successful, independent clinical researcher.